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EP1753716A1 - Sels de base et monohydrates de certains derives d'acide alpha, beta-proprionique - Google Patents

Sels de base et monohydrates de certains derives d'acide alpha, beta-proprionique

Info

Publication number
EP1753716A1
EP1753716A1 EP04755022A EP04755022A EP1753716A1 EP 1753716 A1 EP1753716 A1 EP 1753716A1 EP 04755022 A EP04755022 A EP 04755022A EP 04755022 A EP04755022 A EP 04755022A EP 1753716 A1 EP1753716 A1 EP 1753716A1
Authority
EP
European Patent Office
Prior art keywords
methoxy
methanesulfonyloxyphenyl
propylamino
phenyl
api
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP04755022A
Other languages
German (de)
English (en)
Inventor
Venkata Raghavendra Charyulu Palle
Hari Charan Raju Chennamadhauni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP1753716A1 publication Critical patent/EP1753716A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/02—Guanidine; Salts, complexes or addition compounds thereof

Definitions

  • API active pharmaceutical ingredient
  • the API's solubility, route of administration, dosage size, taste, absorption target or cite of application, metabolic properties and the like often must all be considered. And if the API has stability and/or handling issues, the complexity rises accordingly. Therefore, where possible, it is highly desirable to develop APIs that can be conveniently handled and processed. Chemical stability, solid-state stability and shelf life of the active ingredients are also important considerations.
  • the API and compositions containing it should be capable of being effectively stored over appreciable periods of time, without exhibiting a significant change in the physico-chemical characteristics of active compounds.
  • Crystalline materials for example, can in certain cases be less difficult to handle and to formulate when compared to amorphous forms. But stable crystalline forms that are suitable for formulation and provide sufficient solubility and bioavailabilty are neither necessarily available nor predictable, especially when complex molecules are involved. Moreover, some crystalline materials are not sufficiently stable to ensure that they will not convert to another form, crystalline or not, during manufacturing or storage.
  • Salt formation may improve certain properties such as stability, water solubility and bioavailability. Salts may also influence hygroscopicity and crystallinity. Of course, there is a vast array of possible salts (See WO 03/048116 at 21, line 18-22, line 4) not all salts can be made are equally easy to make or equally advantageous. And not all salts permit the same crystalline forms. The nature of the salts can also influence can the properties of the API and the ability to make a stable dosage form using modern, high speed equipment in an efficient and cost effective manner. And, perhaps most importantly, there must be no unnecessary impediment to the safety and efficacy of the API.
  • the present invention includes the basic salts of ((S)-2-methoxy-3-[4- ⁇ 3- (4-methanesulfonyloxyphenyl) propylamino ⁇ phenyl]propionic acid) (also referred to herein as the basic salts of "(S)MP”) and, in particular, the amino acid salts thereof.
  • a particularly preferred amino acid salt in accordance with the present invention is the arginine salt of (S)MP (the "Arginine salt” or "(S)MP-Arg' 1 .).
  • the invention also encompasses these salts in pure or substantially pure forms.
  • the present invention also includes the monohydrate form of (S)MP as well as the monohydrate of the basic salts of (S)MP, preferably the monohydrate of the amino acid salts of (S)MP, and most preferably (S)MP arginine monohydrate (also referenced as "Arginine salt monohydrate” or "(S)MP-Arg-1H 2 O").
  • the invention also encompasses these monohydrates in a pure or substantially pure forms.
  • Another aspect of the present invention is crystalline forms of the basic salts of (S)MP, whether in monohydrated form or not.
  • a particularly preferred embodiment of the present invention is a crystalline form of (S)MP monohydrate or (S)MP-Arg-1H 2 O.
  • Another aspect of the present invention provides one or more of the foregoing salts and/or monohydrates of (S)MP as the API in a novel pharmaceutical product which is stable and can be efficiently manufactured using traditional high speed equipment.
  • These pharmaceutical products include one of the foregoing as the API salts and/or monohydrates of (S)MP and a pharmaceutically acceptable carrier, diluent, excipient or solvent.
  • Another particularly preferred aspect of the present invention is a pharmaceutical composition that contains, as the API, one or more of the forgoing salts and/or monohydrates of (S)MP and, in particular an Arginine salt and/or Arginine salt monohydrate, in crystalline form, wherein the API is present in an amount of at least about 0.01% by weight of the pharmaceutical composition.
  • Another aspect of the present invention provides a process for the preparation of one or more of the foregoing salts and/or monohydrates of (S)MP and, in particular an (S)MP monohydrate Arginine salt and/or Arginine salt monohydrate, in a crystalline form.
  • DESCRIPTION OF THE DRAWINGS Figure 1 is an infrared spectrum of one batch of Arginine monohydrate of ((S)-2-methoxy-3 - [4- ⁇ 3 -(4-methanesulfonyloxyphenyl) propylamine ⁇ phenyljpropionic acid).
  • Figure 2 is an X-ray powder diffractogram of one batch of Arginine monohydrate of ((S)-2-methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl) propylamino ⁇ phenyl]propionic acid).
  • Figure 3 is a DSC thermogram of one batch of Arginine monohydrate of ((S)-2-methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl) propylamino ⁇ phenyl]propionic acid).
  • Figure 6 is a DSC thermogram of one batch of Arginine salt of ((S)-2- methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl) propylamino ⁇ phenyl]propionic acid).
  • DETAILED DESCRIPTION A compound (also referred to herein as a molecule or chemical) that may be used as a starting material for the preparation of salts and hydrates of the present invention, can be prepared according to known procedures, such as those disclosed in, inter alia, International Publication No. WO 03/048116, which is incorporated herein by reference both in its entirety and for the purpose stated. See in particular Example 14.
  • the salts and monohydrates of the present invention refer to a molecule, per se, unless expressly stated otherwise or as is appropriate under the circumstances. When reference is made to a crystal or crystalline material, a sufficient number of molecules necessary to make a single crystal is contemplated.
  • a pharmaceutical dosage form pharmaceutical product or pharmaceutical composition
  • at least 0.10% by weight of the product is a basic salt of (S)MP or a monohydrate thereof as disclosed herein.
  • the present invention provides basic salts of (S)MP, including those in crystalline form. Examples of basic salts include salts of alkali and earth alkali metals, and amino acid salts (both naturally occurring and synthetic amino acids).
  • the salt is an arginine salt of compound (I) ("Arginine salt"), which was found to be particularly suitable.
  • the present invention encompasses monohydrates of (S)MP and its basic salts as novel materials. Monohydrates ideally include a ratio of one molecule of (S)MP or its basic salt with one molecule of bound water of crystallization. Preferred are monohydrates of basic salts and more preferably Arginine salts of (S)MP. Most preferred are (S)MP monohydrate and Arginine salt monohydrate. Even more preferred is the Arginine salt monohydrate having the characteristics of at least one of Figures 1-3.
  • the present invention also provides a process for preparing basic salts and monohydrates of (S)MP and in particular amino acid salt monohydrates thereof.
  • Arginine monohydrate of (S)MP or a salt thereof is preferably dispersed or dissolved in a suitable solvent, and is reacted with a suitable source of arginine ion in the presence of water, which comprises: (i) refluxing (S)MP, DM water and Arginine 1 ; (ii) further refluxing with additional quantities of a suitable reaction solvent, preferably alcoholic solvent, more preferably, isopropanol; (iii) cooling and filtering the reaction mixture to obtain the Arginine salt hydrate.
  • a suitable reaction solvent preferably alcoholic solvent, more preferably, isopropanol
  • the concentration of (S)MP is preferably in the range of about 60 to 70% weight/weight, more preferably in the range of about 65 to 69%.
  • the concentration of arginine is preferably in the range of about 21 to 39% weight/weight, more preferably in the range of about 26 to 33%.
  • the concentration of water is in the range of about 1.0 to 9.0%. Formation of a monohydrate requires the presence of water at some stage; water may be added as a co-solvent in the above process, e.g., about 5 to 100% water. However, it is also possible to provide sufficient water for monohydrate formation by carrying out the reaction with exposure to atmospheric moisture, or by use of non-anhydrous solvents.
  • a suitable reaction solvent for the preparation of arginine salt monohydrate is a ketone, such as acetone, ethyl methyl ketone, ether such as tetrahydrofuran, dioxane, isopropyl ether, diethyl ether, an alcohol such as methanol, ethanol, propan-2-ol, isopropanol or mixtures thereof and the like.
  • the temperature used in the reaction is maintained in the range of about 30 to 120 0 C, preferably about 30 to 70 0 C.
  • the duration of the reaction is maintained in the range of about 3 to 12 h, preferably, for approximately 5 hours.
  • the crystalline form may be characterized by X-ray powder diffraction pattern (XRPD). X-ray powder diffraction pattern analysis was performed on Rigaku D/Maz-2200 model diffractometer equipped with horizontal goniometer in ⁇ /2 ⁇ geometry.
  • the tube voltage and amperage were set at 50 KV and 34 mA respectively.
  • the divergence and scattering slits are set at 1/2 degree, receiving slit at 015 mm and scattering slit at 1/2 degree.
  • Diffracted radiation is detected by scintillation counter detector, ⁇ to 20 continuous scan at 3 degrees/minutes from 3 to 45 degrees be used.
  • a standard was analyzed to check the instrumental alignment the data was collected and analyzed using. Differential scanning calorimetry was performed using a Shimadzu DSC- 50 calorimeter. The sample was placed into aluminum pan, the weight was accurately recorded, and the pan was covered with lid and left undamped.
  • Each sample was equilibrated and heated (10°C/minute) under nitrogen atmosphere.
  • the crystalline form may also characterized by Fourier transform infra red spectra and recorded in solid state as KBr dispersion.
  • Perkin-Elmer 1600 Fourier transform infra red spectrophotometer was used for characterization.
  • DSC Differential Scanning Calorimeter
  • Arginine monohydrate has infrared spectrum containing peaks at 1630, 1364, 1152, 971, 871 cm “1 .
  • the infrared spectrum is substantially in accordance with Figure 1.
  • an Arginine monohydrate provides X-Ray powder diffraction (XRPD) pattern substantially as shown in Figure 2, and preferably has peaks at 8.44, 17.48, 17.60, 18.84, 21.02, 21.18, 22.02 degrees 2 ⁇ 0.2°2 ⁇ .
  • an Arginine monohydrate provides a Differential Scanning Calorimeter (DSC) spectrum substantially as shown in accordance with Figure 3, and preferably has endotherms at about 92.60, 132.53, 231.80 and 272.22 0 C.
  • DSC Differential Scanning Calorimeter
  • identification of the exact crystalline form of a compound should be based primarily on observed 2 theta angles with lesser importance attributed to relative peak intensities.
  • the peaks reported herein are listed in order of their peak intensities. Thus, the first listed peak has stronger intensity than the second listed peak in the pattern.
  • the 2 theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed 2 theta angles and wavelength using the Bragg equation well known to those of skill in the art.
  • an Arginine salt monohydrate has a melting point in the range of 125 to 140 0 C, such as 127 to 135 0 C, for example 132.5°C.
  • the invention provides Arginine salt monohydrate, characterized in that it provides at least one of an: (i) Infrared spectrum substantially in accordance with Figure 1; (ii) X-Ray powder diffraction (XRPD) pattern substantially in accordance with Table 1 or Figure 2; and/or (iii) Endotherm at about 132.5°C in Differential Scanning Calorimeter (DSC) spectrum substantially in accordance with Figure 3.
  • the arginine salt of (S)MP can be produced by reacting (S)MP or some other salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a suitable source of arginine ion in the presence of a solvent in the 1 : 1 ratio of (S)MP and arginine, which comprises: (i) refluxing compound (I), DM water and arginine (ii) further refluxing with suitable reaction solvent, (iii) azeotropically separating the product obtained by using suitable solvent cooling and filtering the resultant product to obtain arginine salt of (S)MP.
  • the concentration of (S)MP is preferably in the range of about 60 to 80% weight/weight, more preferably in the range of about 65 to 75%.
  • the concentration of arginine is preferably in the range of about 20 to 40% weight/weight, more preferably in the range of about 25 to 35%.
  • a suitable reaction solvent for the preparation of anhydrous form is a ketone, such as acetone, ethyl methyl ketone, ether such as tetrahydrofuran, dioxane, diisopropyl ether, diethylether, an alcohol, such as methanol, ethanol, propan-2-ol.
  • the solvent used during the azeotropic removal of water is selected from a hydrocarbon such as xylene, toluene, an ester such as ethyl acetate, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloroniethane, dichloroethane and the like.
  • the temperature used in the reaction is maintained in the range of about 30 to 12O 0 C, preferably about 30 to 7O 0 C.
  • the duration of the reaction is maintained in the range of about 3 to 12 h.
  • the present invention provides arginine salt of (S)MP in nonhydrated form ((S)MP-Arg) as a novel compound, which is characterized by at least one of an: ' (i) Infra red spectrum containing peaks at 1638, 1364, 1173, 1152, 971, 871 cm- 1 ; (ii) X-Ray powder diffraction (XRPD) pattern containing peaks at 16.40, 16.82, 17.38, 19.28, 19.70, 20.22, 20.56 degrees 2 ⁇ ; and/or (iii) Endotherm at about 192.9 0 C and 228.7°C.
  • the (S)MP- Arg provides an infrared spectrum substantially in accordance with Figure 4.
  • (S)MP-Arg is characterized by an infrared spectrum containing peaks at about 1638, 1364, 1173, 1152, 971, 871 cm 4 .
  • the (S)MP- Arg provides X-Ray powder diffraction (XRPD) substantially in accordance with Table 2 or Figure 5.
  • the (S)MP- Arg characterized by an X-ray powder diffraction(XRPD) pattern containing peaks at about 16.40, 16.82, 17.38, 19.28, 19.70, 20.22, 20.56 degrees 2 ⁇ O.2°2 ⁇ .
  • the (S)MP-Arg provides a Differential Scanning Calorimeter (DSC) spectrum substantially in accordance with Figure 6.
  • the (S)MP- Arg is characterized by a Differential Scanning Calorimeter (DSC) spectrum containing endotherm at about 192.9 and 228.7°C.
  • the (S)MP-Axg has a melting point in the range of about 185 to 200 0 C, such as 187 to 195 0 C, for example, 192.9°C.
  • the invention provides a (S)MP-Arg characterized in that it provides at least one of an: (i) Infrared spectrum substantially in accordance with Figure 4; (ii) X-Ray powder diffraction (XRPD) pattern substantially in accordance with Figure 5; and/or (iii) Endotherm at about 192.9°C in Differential Scanning Calorimeter (DSC) spectrum substantially in accordance with Figure 6.
  • XRPD X-Ray powder diffraction
  • DSC Differential Scanning Calorimeter
  • the invention also provides a process for the conversion of the Arginine salt monohydrate to (S)MP-Arg, wherein the Arginine salt monohydrate is suspended in a suitable solvent and refluxed to remove water azeotropically, which comprises: (i) refluxing Arginine salt monohydrate with a suitable solvent to azeotropically remove water content, (ii) cooling and filtering the resultant product to obtain Arginine salt of compound (I).
  • the solvent used during the azeotropic removal of water is selected from a hydrocarbon such as xylene, toluene, an ester such as ethyl acetate, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane, dichloroethane and the like.
  • the temperature used in the reaction is maintained in the range of about 30 to 8O 0 C, preferably about 30 to 7O 0 C.
  • the duration of the reaction is maintained in the range of about 3 to 12 h.
  • the invention also provides a process for the conversion of the (S)MP- Arg to Arginine monohydrate, wherein the (S)MP- Argis suspended in a suitable solvent in the presence of water, and optionally thereafter as required: (i) refluxing (S)MP-Arg and DM water, (ii) further refluxing with suitable reaction solvent, (iii) cooling and filtering the reaction mixture to obtain the Arginine monohydrate.
  • a suitable reaction solvent for the preparation of Arginine monohydrate is a ketone, such as acetone, ethyl methyl ketone an ether such as tetrahydrofuran, dioxane, isopropyl ether, diethyl ether, an alcohol such as methanol, ethanol, propan-2- ol, isopropanol or mixtures thereof and the like.
  • the temperature used in the reaction is maintained in the range of about 30 to 8O 0 C, preferably about 30 to 7O 0 C.
  • the duration of the reaction is maintained in the range of about 3 to 12 h.
  • Recovery of the desired compound may comprise crystallization from a solvent, conveniently the reaction solvent, usually assisted by cooling.
  • an improved yield of the badic salts may be obtained by evaporation of some or all of the solvent or by crystallization at elevated temperature, for example about 75 0 C, followed by slow cooling.
  • Co-solvents can be added to reduce the solubility of the product in the solvent system to provide a good yield, e.g. diethyl ether, diisopropyl ether and heptane. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the product form. Crystallization may also be initiated by, in one non-limiting example, seeding.
  • T onse t is generally determined by Differential Scanning Calorimetry and has a meaning generally understood in the art, as for example expressed in "Pharmaceutical Thermal Analysis, Techniques and Applications", Ford and Timmins, 1989 as "The temperature corresponding to the intersection of the pre-transition baseline with the extrapolated leading edge of the transition".
  • “Substantially pure” means the material that contains about 95-99.8%, at least about 95%, preferably about 98%, more preferably about 99.8% of the compounds of the present invention.
  • “Pure” means greater than 99.8% of the compound is the desired compound.
  • the present invention also provides pharmaceutical compositions comprising the basic salts of (S)MP, (S)MP monohydrate and monohydrated forms of basic salts of (S)MP, and more preferably (S)MP- Arg and (S)MP- 1H2O mixed with, solubilized or dispersed in a pharmaceutically acceptable carrier, diluent, solvent and /or the excipient.
  • a pharmaceutically acceptable carrier diluent, solvent and /or the excipient.
  • the basic salt of (S)MP, (S)MP monohydrate or monohydrated form of a basic salt of (S)MP (collectively the "API"
  • the API should be present in an amount of at least about 0.10% by weight of the pharmaceutical product.
  • APIs and in particular, Arginine salt monohydrate or Arginine salt are normally administered in unit dosage form.
  • the API may be administered by any suitable route but usually by the oral or parenteral routes.
  • the compound will normally be employed in the form of a pharmaceutical composition in association with a pharmaceutical carrier, diluent and/or excipient, although the exact form of the composition will naturally depend on the mode of administration.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl toluenesulfonate.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the active compound in a vehicle and filter sterilizing before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • Step (ii) To a DCM (550 mL) solution of 3-(4-hydroxyphenyl)propanol (17 g, 1.0 eq, 111.8 mmol), obtained in the step (i) and triethylamine ( 93.3 mL, 6.0 eq, 670.8 mmol) was added methanesulfonyl chloride ( 26 mL, 3.0 eq, 335.4 mmol) dropwise at O 0 C.
  • reaction mixture was stirred at RT for 16 h, after that it was worked up by diluting with excess DCM and washing the organic layer with dil. HCl, water and brine. The organic layer was dried (Na 2 SO 4 ) and concentrated. Desired product from the crude mass was purified by recrystallization from diisopropylether. The remaining mother liquor was condensed and was chromatographed (ethyl acetate/hexanes) to obtain further amount desired compound (total yield 20.8 g, 61%) as white solid. Mp: 60-62 0 C.
  • Step(viii) Preparation of (S) 3-Methoxy -3-[4- ⁇ 3-(4-methanesulfonyoxy phenyl)propylamino ⁇ phenyl]propionic acid]
  • reaction mixture was condensed, diluted with water and acidified (pH at 3) with aq. HCl. Desired acid was precipitated out from aqueous layer, which was then filtered out. If the precipitated acid was not pure enough by TLC, it was chromatographed using MeOH and CHCl 3 as eluents to obtain the pure acid as white solid (2.5 g, 79%).
  • Mp 90-92 0 C. [ ⁇ ]d: -16° (c 1.0, MeOH).
  • Tonset of Arginine hydrate' The T onse t was determined by Differential Scanning Calorimetry. Melting endotherm was observed at 92.6°C, 132.53 0 C, 231.8O 0 C, 272.22°C
  • EXAMPLE 3 L- Arginine salt of (S)-2-methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl) propylamino ⁇ phenyl ⁇ propionicacid (Arginine salt) (S)-2-Methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl)propylamino ⁇ phenyl ⁇ propionicacid, (10 grams) and DM water (30 mL) were refluxed.
  • L- Arginine (0.426 grams) was added to the reaction mixture at 25-3O 0 C in about 5 minutes and maintained at the same temperature for 4-5 hours.
  • Isopropanol 120 mL was added to the reaction mixture and continued stirring further for 2 to 4 hours.
  • the precipitated product was filtered, dried at 6O 0 C for 8-10 hours and further refluxed with toluene to remove water azeotropically.
  • the X-Ray Powder Diffractogram pattern of the product ( Figure 5) was recorded using the following acquisition conditions: Tube anode: Cu, Generator tension: 50 kV, Generator current: 34 mA, Start angle: 3.0°2 ⁇ , End angle: 45°2 ⁇ , Step size: 0.02°2 ⁇ , speed: 3 deg./min. Characteristic XRPD angles and relative intensities are recorded in Table 2. TABLE 2 Tonset of 'Arginine hydrate': The T onse t was determined by Differential Scanning Calorimetry. Melting endotherm was observed at 192.93°C, 228.69 0 C, 272.22°C.
  • L-Arginine salt of (S)-2-Methoxy-3-[4- ⁇ 3-(4-methanesulfonyloxyphenyl) propylaminojphenyl] propionic acid (10 grams) and water (40 mL) were heated at 50- 6O 0 C for 4-5 hours.
  • EXAMPLE 6 a) Determination of hPP ARa activity
  • Ligand binding domain of hPPAR ⁇ was fused to DNA binding domain of Yeast transcription factor Gal 4 in eucaryotic expression vector.
  • superfect Qiagen, Germany
  • HEK-293 cells are transfected with this plasmid and a reporter plasmid harboring the luciferase gene driven by a GAL4 specific promoter. Compound can be added at different concentrations after 42 hrs of transfection and incubated overnight.
  • Luciferase activity as a function of compound binding/activation capacity of PP ARa will be measured using Packard Luclite kit (Packard, USA) in Top Count (Ivan Sadowski, Brendan Bell, Peter Broag and Melvyn Hollis. Gene. 1992. 118: 137-141; Superfect Transfection Reagent Handbook. February 1997. Qiagen, Germany).
  • b) Determination of hPPAR ⁇ activity Ligand binding domain of hPPAR ⁇ l is fused to DNA binding domain of Yeast transcription factor GAL4 in eucaryotic expression vector.
  • Liver microsome bound reductase is prepared from 2% cholestyramine fed rats at mid-dark cycle. Spectrophotometric assays are carried out in 100 mM KH 2 PO 4 , 4 mM DTT, 0.2 mM NADPH, 0.3 mM HMG CoA and 125 ⁇ g of liver microsomal enzyme. Total reaction mixture volume was kept as 1 ml. Reaction was started by addition of HMG CoA.
  • Reaction mixture is incubated at 37 0 C for 30 min and decrease in absorbance at 340 nm was recorded. Reaction mixture without substrate was used as blank (Goldstein, J. L and Brown, M. S. Progress in understanding the LDL receptor and HMG CoA reductase, two membrane proteins that regulate the plasma cholesterol. J. Lipid Res. 1984, 25: 1450 - 1461). The test compounds will inhibit the HMG CoA reductase enzyme.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne de nouveaux sels d'acide (S)-2-méthoxy-3-[4-{3-(4-méthanesulfonyloxyphényl)propylamino}phényl] proprionique, y compris un sel arginine de monohydrate d'acide (S)-2-méthoxy-3-[4-{3-(4-méthanesulfonyloxyphényl)propilamino}phényl] proprionique; un sel arginine d'acide(S)-2-méthoxy-3-[4-{3-(4-méthanesulfonyloxyphényl)propilamino}phényl] proprionique; et un monohydrate d'acide (S)-2-méthoxy-3-[4-{3-(4-méthanesulfonyloxyphényl)propilamino}phényl] proprionique. On décrit divers aspects et modes de réalisation. L'invention concerne en outre des compositions contenant de nouveaux sels d'acide (S)-2-méthoxy-3-[4-{3-(4-méthanesulfonyloxyphényl)propilamino}phényl] proprionique.
EP04755022A 2004-06-10 2004-06-10 Sels de base et monohydrates de certains derives d'acide alpha, beta-proprionique Pending EP1753716A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2004/018620 WO2006001795A1 (fr) 2004-06-10 2004-06-10 Sels de base et monohydrates de certains derives d'acide alpha, beta-proprionique

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EP1753716A1 true EP1753716A1 (fr) 2007-02-21

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EP (1) EP1753716A1 (fr)
CA (1) CA2570820A1 (fr)
WO (1) WO2006001795A1 (fr)

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Publication number Priority date Publication date Assignee Title
UA82835C2 (en) * 2001-12-03 2008-05-26 Reddys Lab Ltd Dr ?-aryl-?-oxysubstituted propionuc acid derivatives and pharmaceutical composition based thereon

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Title
See references of WO2006001795A1 *

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CA2570820A1 (fr) 2006-01-05

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